Abstract Approximately ?one in ten U.S. adults suffer from daily urinary incontinence; most of those affected are women? (NIDDK). Hence 12.6 million American women are afflicted by this distressing and socially stigmatizing problem, at a cost of $88.2 billion dollars annually. Despite the importance of this condition, cure rates in NIH- sponsored trials for stress and urge incontinence remain at 50% or lower. Why? The current conceptual framework on which treatments are based maintains that 1) stress incontinence is caused by poor urethral support, and 2) urge incontinence is caused by abnormal bladder contractility. Paradigm-shifting research by our group shows that the urethral sphincter complex, long overlooked as a causal factor, is responsible for 50% of stress incontinence and also plays a critical role in urge incontinence. Progress in understanding how the urethral closure mechanism works is currently hindered by two factors: 1) current testing strategies that are based on outmoded, simplistic, and artifact-prone 1960s technology, and 2) the lack of a detailed understanding of urethral structure-function relationships needed to guide research. AIM 1: Develop a state-of-the-art battery of urethral sensorimotor and vascular assessment tools: We will produce and validate novel measurement strategies using state-of-the-art sensor and advanced imaging strategies. These tools will include: a) an ultraflexible, microscale, multisite urethral pressure catheter; b) a physiologic urethral sensory testing apparatus; and c) a miniature wearable uroflowmeter and a daily activity monitor. AIM 2: Develop advanced ultrasound imaging equipment and strategies: The structure and function of the urethra is easily accessed by ultrasound, yet strategies and equipment to evaluate it are limited. In this Aim, we will develop: B-mode for dynamic anatomy, Doppler for vascular flow quantification, and elastography for urethral wall mechanical properties to measure real-time urethral kinematics that can be used by AIMS 1 & 3. AIM 3: Develop a multiscale 3D anatomical atlas and high-fidelity urethral multiphysics computer model for simulating how changes in individual structures and the effects of age and disease processes affect urethral function. We will a) produce the first in vitro 3D multiscale probability map and in vivo high-resolution MR scans of the female urethra. These data, along with emerging data from AIMS 1 & 2, will be used to b) create and validate the first finite element multiphysics urethral model that can be used by researchers to investigate how changes in individual urethral structural and functional parameters affect urethral closure pressure. The technical and conceptual tools provided by this work will stimulate research and launch hypothesis testing to clarify how the continence margin is determined and how age, diabetes, childbirth, race, genetics, and other factors affect urethral failure in women. This work will reveal currently unexplored therapeutic targets and bring science to the urethra's critical, but long overlooked, aspect of continence function.